Background: Simple renal cysts usually have benign clinical features. We report a rare case of papillary renal cell carcinoma (RCC) associated with a large recurrent simple cyst following sclerotherapy. Case Presentation: A 47-year-old Japanese woman received minocycline sclerotherapy for a large (9 cm in diameter) simple left renal cyst in May 2005. The cyst regrew, and second-line sclerotherapy with ethanol was performed in November 2005. Three years later, she developed papillary RCC on the wall of the recurrent renal cyst. Radical nephrectomy was performed, but the patient died of metastatic disease 15 months after surgery. Conclusion: Malignant transformation from recurrent simple renal cyst to RCC may occur in the years following sclerotherapy, underscoring the need for long-term follow-up.